Molecular studies of sunscreen in humans David Whiteman
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1 Molecular studies of sunscreen in humans David Whiteman Deputy Director Head, Cancer Control Group
2 Queensland University of Technology Elke Hacker Zac Boyce Acknowledgements QIMR Berghofer David Whiteman Catherine Olsen Sam Vaartjes Louise Wilson Nick Hayward Adele Green Thomas Pollack University of the Sunshine Coast Cancer Council Queensland Michael Kimlin Pathology services H Konrad Mueller QIMR Berghofer Medical Research Institute 2
3 Overview 1. Sunscreen & skin cancer: epidemiologic challenges 2. DNA damage in skin cancer 3. An experiment 4. Systematic review 5. Summary and conclusions QIMR Berghofer Medical Research Institute 3
4 Sunscreen for skin cancer prevention? Epidemiologic data Observational studies intractable confounding Confounding by indication Queensland Institute of Medical Research 4
5 Sunscreen for skin cancer prevention? Epidemiologic data Randomized trials only one Confounding by indication Queensland Institute of Medical Research 5
6 Sunscreen for melanoma prevention? First author Cases/controls Exposure Location Study design (publication year) (Cohort size) assessment Green et al Australia RCT 33/1621 Assigned Cho et al. 2005* USA Cohort 535/178,155 Self-report (F:152,949; M:25,206) Lazovich et al USA Case-control 1167/1101 Self-report Youl et al. 2002* Australia Case-control 201/205 Self-report Westerdahl et al Sweden Case-control 571/913 Self-report Whiteman et al. 1997* Australia Case-control 52/156 Self-report Autier et al. 1995* Germany, Case-control 418/438 Self-report Belgium, France Westerdahl et al Sweden Case-control 400/640 Self-report Holly et al USA Case-control 452/930 Self-report Herzfeld et al. 1993* USA Case-control 324/415 Self-report Beitner et al. 1990* Sweden Case-control 523/505 Self-report Osterlind et al Denmark Case-control 474/926 Self-report Holman et al. 1986* Australia Case-control 507/507 Self-report QIMR Berghofer Medical Research Institute 6
7 Sunscreen for melanoma prevention? RCT Source: Olsen et al. submitted (2017) QIMR Berghofer Medical Research Institute 7
8 Sunscreen for melanoma prevention? RCT Observational Source: Olsen et al. unpublished QIMR Berghofer Medical Research Institute 8
9 UV damage in skin cells Cyclobutane pyrimidine dimers (CPD = TT, CT, TC) Pyrimidine (6-4) pyrimidone photoproducts (6-4TT) If photolesions not repaired fixed mutation in daughter cells QIMR Berghofer Medical Research Institute 9
10 Biomarkers as an intermediate endpoint Experimental data Biomarker / mutation studies Queensland Institute of Medical Research 10
11 Effect of sunscreen on molecular & cellular markers Queensland Institute of Medical Research 11
12 Objectives 1. Assess DNA damage in human skin in vivo before and after UVR exposure (2 MED) 2. Assess melanocyte proliferation in human skin in vivo before and after UVR exposure (2 MED) 3. Determine whether biomarkers affected by sunscreen QIMR Berghofer Medical Research Institute 12
13 Design of study SCREEN for eligibility / pigmentation Baseline biopsy control skin (Day 1) UV exposure - 2 MED at 2 sites 3 biopsies at 24 hr (Day 2) -Control, UV, UV + sunscreen Baseline 24 hours 14 days 3 biopsies at 14 days (Day 14) -Control, UV, UV + sunscreen Control UVR Sunscreen + UVR QIMR Berghofer Medical Research Institute 13
14 Participants 57 healthy Caucasian volunteers Mean age 25 years (range yrs). Fitzpatrick skin type 9% skin type 1 54% skin type 2 37% skin type 3 QIMR Berghofer Medical Research Institute 14
15 Biomarkers measured Biomarker Erythema CPD ki67 p53 Melanocyte counts Biological interpretation Acute inflammation UV-specific damage to DNA sequence Marker of cell proliferation Overexpression indicates DNA damage Melanocyte proliferation QIMR Berghofer Medical Research Institute 15
16 Dual staining to observe effects Proliferating Cells - Melanocyte QIMR Berghofer Medical Research Institute 16
17 Effect of sunscreen on erythema QIMR Berghofer Medical Research Institute 17
18 Effect of sunscreen on CPDs Effect of UVR Effect of sunscreen ~100%
19 Effect of sunscreen on p53 Effect of UVR Effect of sunscreen >100% Baseline p53 QIMR Berghofer Medical Research Institute 19
20 Effect on melanocyte counts Effect of UVR Effect of sunscreen ~100%
21 Summary of findings SPF 30+ sunscreen blocked virtually all UV-induced parameters measured: Erythema P53 CPD Melanocyte proliferation QIMR Berghofer Medical Research Institute 21
22 Sunscreen and biomarkers systematic review Source: Olsen et al. Photoderm Photoimmunol Photomed (2017) QIMR Berghofer Medical Research Institute 22
23 Screening Sunscreen and biomarkers systematic review Eligibility Identification Records identified Pub Med: records screened for LANGUAGE 150 records screened for CONTENT 94 records screened for SUNSCREEN 43 records screened for DNA MUTATIONS 40 records screened for INCLUSION CRITERIA 10 ELIGIBLE STUDIES Not human (n = 0) Not in English (n =4) Reviews (n = 56) No exposure data (n = 51) No outcome data (n = 3) Other exclusion (n = 30) Source: Olsen et al. Photoderm Photoimmunol Photomed (2017) QIMR Berghofer Medical Research Institute 23
24 Sunscreen and biomarkers systematic review 10 ELIGIBLE STUDIES Natural UVR (n = 2) Observational UVB (n = 2) Experimental SSUVR (n = 6) Experimental Source: Olsen et al. Photoderm Photoimmunol Photomed (2017) QIMR Berghofer Medical Research Institute 24
25 Sunscreen and biomarkers systematic review First author (year) DNA markers Sample size Young 1991 Unscheduled DNA synthesis 18 Van Praag 1993 TT dimer 10 Bykov 1998 TT dimer 14 SPF 10 Young 2000 TT dimer, (6-4)PP 8 Ling 2001 TT dimer, P53 4 Liardet 2001 CPD, p53, 8OHDG 8 Mahroos 2002 TT dimer 18 Hacker 2013 CPD, p53, Ki67, cell counts 57 Sunscreen regimen UVB sunscreen +/- 5- MOP SPF mins prior SPF 4 (UVB vs UVA filters) 20 mins prior SPF 15 sunscreen 15 mins prior SPF mins prior SPF mins prior SPF mins prior Source: Olsen et al. Photoderm Photoimmunol Photomed (2017) QIMR Berghofer Medical Research Institute 25
26 Sunscreen and biomarkers systematic review First author (year) DNA markers Sample size Young 1991 Unscheduled DNA synthesis 18 Van Praag 1993 TT dimer 10 Sunscreen regimen UVB sunscreen +/- 5- MOP SPF mins prior Biomarker Bykov 1998 TT dimer 14 SPF 10 Young 2000 TT dimer, (6-4)PP 8 Ling 2001 TT dimer, P53 4 Liardet 2001 CPD, p53, 8OHDG 8 Mahroos 2002 TT dimer 18 Hacker 2013 CPD, p53, Ki67, cell counts 57 SPF 4 (UVB vs UVA filters) 20 mins prior SPF 15 sunscreen 15 mins prior SPF mins prior SPF mins prior SPF mins prior Source: Olsen et al. Photoderm Photoimmunol Photomed (2017) QIMR Berghofer Medical Research Institute 26
27 Summary of findings Literature not extensive Sunscreen (SPF 15+) attenuates short- (24 hrs) and mediumterm (14 d) biologic effects of UVR in human skin Higher SPF appears to confer higher attenuation than lower SPF QIMR Berghofer Medical Research Institute 27
28 Conclusions Modern sunscreens prevent biological damage to human skin when applied before UVR exposure QIMR Berghofer Medical Research Institute 28
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